Apolipoprotein D (ApoD) has many actions critical to maintaining mammalian CNS function. It is therefore significant that levels of ApoD have been shown to be altered in the CNS of subjects with schizophrenia, suggesting a role for ApoD in the pathophysiology of the disorder. There is also a large body of evidence that cortical and hippocampal glutamatergic, serotonergic and cholinergic systems are affected by the pathophysiology of schizophrenia. Thus, we decided to use in vitro radioligand binding and autoradiography to measure levels of ionotropic glutamate, some muscarinic and serotonin 2A receptors in the CNS of ApoD-/- and isogenic wild-type mice. These studies revealed a 20% decrease (mean ± SEM: 104 ± 10.2 vs. 130 ± 10.4 fmol/mg ETE) in the density of kainate receptors in the CA 2–3 of the ApoD-/- mice. In addition there was a global decrease in AMPA receptors (F1,214 = 4.67, p < 0.05) and a global increase in muscarinic M2/M4 receptors (F1,208 = 22.77, p < 0.0001) in the ApoD-/- mice that did not reach significance in any single cytoarchitectural region. We conclude that glutamatergic pathways seem to be particularly affected in ApoD-/- mice and this may contribute to the changes in learning and memory, motor tasks and orientation-based tasks observed in these animals, all of which involve glutamatergic neurotransmission.